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Spill and kill

As necrosis progresses (left to right), protease-containing lysosomes enlarge, aggregate at the nucleus, and then fuse to surround the swollen nucleus of the dying neuron.

Lysosomes spill their guts and kill their host cells, as revealed on page 231. Artal-Sanz et al. show that cells are more likely to escape a necrotic death sentence if they contain less acidic lysosomes.

Necrosis—considered the unprogrammed counterpart to apoptotic death—is the deadly result of a severe and abrupt loss of energy, nutrients, or oxygen. These stimuli create sudden alterations in intracellular pH or ion levels that ultimately turn on destructive proteases within the cell.

Some of these proteases, such as cathepsins, work best at very low pH. Acidification of the cell occurs during necrosis. Further, a pump that acidifies lysosomes, where cathepsins are normally sequestered, is required for necrosis in worms.

The new study shows that lysosomes are themselves needed during necrosis. By interfering with lysosomal biogenesis, the authors hindered neuronal necrosis in worms. Mutations that created abnormally large lysosomes, by contrast, aggravated necrosis.

Lysosomes also have to be acidified to be necrosis inducing. The authors found that alkalization of the organelles using weak bases suppressed necrosis. It also further reduced death in mutant neurons with unusually low amounts of cathepsins.

The authors suspect that lysosomes start leaking their contents at early stages of necrosis. Their idea is supported by past evidence that the protease calpain—which is activated by high Ca²⁺ levels during necrosis—damages lysosomal membranes. The damage might open the door for a slow escape of cathepsin and H⁺—thus both freeing proteases that dismantle the cell and creating the acidic environment in which they thrive. At later stages of death, the authors saw, lysosomes ruptured completely.

Necrosis dominates the neuronal death caused by ischemia during a stroke. Perhaps the damage can be minimized if therapies are devised to prevent lysosomal acidification locally. The drugs would probably only be beneficial, however, if administered very shortly after the stroke.

Nicole LeBrasseur

lebrasn{at}rockefeller.edu

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This Article Full Text (PDF, 921K) PPT slides of all figures Alert me when this article is cited Services Email this article Similar articles in this journal Alert me to new content in the JCB Download to citation manager Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by LeBrasseur, N. Search for Related Content PubMed Articles by LeBrasseur, N. Social Bookmarking                            What's this?